17beta-substituted-3alpha-amino-5alpha-androstanes



United States Patent 3,264,326 17fl-SUBSTITUTED-3a-AMINO-Sa-ANDROSTANESDonald E. Clark, Norristown, and Norman H. Grant,

Wynnewood, Pa, assignors to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware No Drawing. Filed Apr. 29, 1964,Ser. No. 363,633 4 Claims. (Cl. 260-397) wherein R is selected from thegroup consisting of N'I-ICOOH and NH together with the nontoxic,pharmacologically acceptable, acid addition salts thereof. The newcompounds of the present invention are prepared by first reactingfuntumine with hydrazoic acid, generated from sodium azide in thepresence of HCl. The free base is then obtained by dissolving theresulting salt with aqueous base, such as sodium hydroxide. The product(wherein R=NHCOCH then serves as an intermediate to the final productwherein R of Formula I is NH The latter compound is obtained byhydrolysis of the 17,8-acetamido by refluxing the latter with dilutemineral acid. The free base of the diamine is obtained by adjustment ofthe pH with base.

The reaction by which the new compounds of the present invention areobtained may be more readily understood by reference to the reactionsequence below:

According to the foregoing sequence, a mixture of 7 3,254,3-Zb PatentedAugust 2, 1966 ice 2 hours of stirring, the resulting precipitate(17fl-acetamido-Bu-amino-lia-tandrostane, III) is removed. (It iswashed, redissolved, acidified and evaporated to dryness. The free baseis obtained on dissolving in water and neutralizing with base.Hydrolysis of III, by refluxing for a period oi from about 10 to about20 hours 'with dilute sulfuric acid results in the diamine IV. The Ifreebase of the di-amine IV (Su androstaneru-17fi-diamine) is precipitatedby adjusting the pH to about 11.5 with base. The final product may thenbe purified according to conventional technique.

The funtumine starting material (II) is prepared according to thereaction described in Compt. rend. Acad. Sci. 240, 3076, 1.958.

As described above, the new compounds of the present invention may beused in the dorm of their pharmaceutically acceptable acid additionsalts. Such salts are obtained by conventional practice by treating .thefree base form of the compounds described with an acceptable organic orinorganic acid. Suitable acids for this purpose include hydrobromic,sulfuric, phosphoric, nitric, benzo'ic, methyl sulfonic, p-tolylsulfonic, benzene sill-tonic, naphthalene sulfionic, salicylic,iglycolic, acetic, male-ic, succinic, tartaric, stearic, palmitic,citric, glutaric, lactic and the like.

The new compounds of the present invention are usevflll and eifectiveagainst a variety of microorganisms including both gram-positive andgram-negative species. Specifically, the new compounds of the presentinvention have been found to be efiective against Bacillus subtilis,Escherichia coli, Staphylococcus aureus, Lactobacillus casei as well asother microorganisms. The effectiveness of these new compounds againstthe microorganisms identified has been measured according to standardand accepted test procedures.

'Reference now to the specific examples which follow will provide abetter understanding of the new compounds of the present invention andthe manner in which they are prepared.

Example I Anhydrous hydrogen chloride is bubbled through a mixtureconsisting of 5 grams of lfuntumine and 13.8 grams of sodium azidestirring at 11 C. in 50 ml. of benzene. Ahter 40 minutes, the stirringis stopped, and the system chilled. The precipitate is collected, andwashed first with aqueous sodium bicarbonate and then water. It isdissolved in ethanol, passed through a Dowex 1 (OH) column, acidifiedwith aqueous hydrochloric acid, and evaporated to dryness. The free baseis prepared from the hydrochloride by dissolving in water andneutralizing with sodium hydroxide. The resultant precipitate is washedwith water and dried.

Example II Hydrolysis of 17,8-acetamido-3a-amino-Sa-androstane iscarried out by refluxing 1.8 grams -for 11.5 hours in 5% H The mixtureis filtered, and the free base of the d-iamine is precipitated byadjusting the filtrate pH to 11.5 with NaOH. The precipitate, collectedafter chilling is washed with .water, dissolved in ethanol, treated withgaseous HCl, evaporated to dryness, extracted into water, and finallyevaporated to dryness, giving 1.1 grams of product.

While the foregoing invention has been described with some degree ofparticularity in the specific examples set forth above, it is to beunderstood that the invention is not to be limited thereby but is onlyto be limited by the claims appended hereto.

The invention claimed is:

1. 17 8acetarnido-3u-amino-5a-androstane.

Q. The method of preparing 17B-acet-amido-3a-amino- Sa-andmsta ne whichcomprises passing hydrogen'chloi-p ride through a mixture "offu'ntinnine andIsodi umazide. in the presence of :an inert solvent,chilling the mixture and recovering the desired product.

3. The method of preparing 5O6-331dIOStaI'1e130g17fi-di amine whichcomprises treating 17 B-acetamido3a-amin0-,

Su-androstane with dilute acid, filtering the mixture and recovering thedesired product by adjusting the filtrate pH to 11.5. r

dition salts of the eomp ound ofelaim :1.

References Cited by: the Examiner 5 Crabbe. et al.: Bull. Soc. Chim.Belg., 71' pp. 203-216 (1952), p.; 208 relied on; V

LEWIS GOTTS, Primary Examiner. HENRY A. FRENCH,'Assistant Examiner.

1. 17B-ACETAMIDO-3A-AMINO-5A-ANDROSTANE.